3-pyridyl-1,2,4-benzothiadiazine-1,1-dioxide for lowering uric acid levels

ABSTRACT

METHOD FOR DECREASING THE CONCENTRATION OF URIC ACID IN THE BLOOD AND URINE OF A MAMMAL BY THE ADMINISTRATION OF A 3-PYRIDYL-1,2,4-BENZOTHIADIAZINE-1,1-DIOXIDE PRODUCT OR A 3,4-DIHYDRO DERIVATIVE. PRODUCTS EMPLOYED IN THIS METHOD OF TREATMENT ARE PREPARED BY CONVENTIONAL PROCEDURES EMPLOYING RING CLOSURE OF THE APPROPRIATE ORTHANILAMIDE. THE PRODUCTS EFFECT THE LOWERING OF THE URIC ACID LEVEL BY VIRTUE OF THEIR XANTHINE OXIDASE INHIBITING PROPERTIES.

United States Patent Oflice' 3,816,626 Patented June 11, 1974 3 816 626 3-PYRIDYL 1,2,4 liENiOTI-IIADIAZINE-Ll-DI- OXIDE FOR LOWERING URIC A'CID LEVELS Frederick C. Novello, Berwyn, Pa., assignor to Merck &

Co., Inc., Rahway, NJ. No Drawing. Filed June 29, 1972, Ser. No. 267,278 Int. Cl. A61k 27/00 US. Cl. 424-246 15 Claims 7 Y ABSTRACT OF THE DISCLOSURE Method for decreasing the concentration of uric acid in the blood and urine of a-mammal by the administration of a 3-pyridy1-1,2,4-benzothiadiazine-l,l-dioxide product or a 3,4-dihydro derivative. Products employed in this method of treatment are prepared by conventional procedures employing ring closure of the appropriate orthanilamide..The products effect the lowering of the uric acid level -by virtue of their xanthine oxidase inhibiting properties.

and pharmacologically acceptable salts thereof wherein X is. selected from halogen,'particularly chloro or bromo, trifiuoromethyl and C alkyl; Y represents hydrogen, chloro and C .alkyl; R represents pyridyl, its quaternary ammonium salt or N-oxide, and monoor di-substituted pyridyl wherein the substituents can be the same or different groups selected from hydroxy, C alkyl, C, al-koxy, amino and acetylamino; and R is C alkyl, preferably methyl.

The active products can be prepared by one or another of the'well known'procedures for making benzothiadia'zine compounds'of structures I and II.

In general, the benzothiadiazine compounds of structure I can be prepared by reacting a mixture of the appropriate orthanilamide derivative with the pyridine carboxylic acid halide which, for practical purposes, can be the acid chloride. The acid chloride can be preformed and employed in the reaction or it can be prepared in situ by the addition of phosphorus oxychloride to a mixture of the orthanilamide and the pyridine carboxylic acid. When the acid chloride is'preformed, the reaction advantageously isconducted in the presence of an inert solvent such as dioxa'ne, tetrahydrofuran, dimethylformamide, and the like and is facilitated by heating up to the reflux temperature of the reaction mixture. When the pyridine carboxylic acid chloride is formed in situ, the phosphorus oxychloride serves not only to form the acid chloride but as solvent as well.

A conventional method for preparing the 3,4-dihydrobenzothiadiazine of structure II above comprises reacting a mixture of the appropriate orthanilamide derivative with the pyridine carboxaldehyde, generally in the presence of a mineral acid. In those instances where a substituent is attached to either the pyridyl moiety or the orthanilamide moiety that would be removed under acid conditions the reaction can take place in the presence of base such as an alkali metal hydroxide or the reaction time in the presence of a mineral acid can be closely followed to determine the point at which cyclization is effected. When acid labile groups are present the reaction generally is conducted at ambient temperature in the presence of mineral acid. When an alkali metal hydroxide is employed or when no acid labile groups are present the reaction mixture can be heated up to reflux conditions. It is well known that the 3,4-dihydro compounds (II) can be prepared from the dehydro compounds (I) by reduction employing hydrogen in the presence of ruthenium or by treatment with an alkali metal borohydride or an equivalent reducing agent capable of reducing the double bond. Various methods of reducing the double bond have been described in the literature and any one of these methods can be employed in converting the products of structure I to the products of structure II.

Pharmacologically acceptable salts generally are the alkali metal salts which may be prepared by conventional methods, for example by treatment with an alkali metal hydroxide, e.g. sodium or potassium hydroxide, in a solvent such as a lower alkanol or in water and evaporating the solvent or by reacting the free compound, for example, in an ether, e.g. dioxane or diethyleneglycol dimethyl ether solution with an alkali metal hydride or amide and removing the solvent. Monoor poly-salts may be obtained.

As the active products of the method of this invention are inhibitors of xanthine oxidase, they effectively decrease the concentration of uric acid in the blood and urine of mammals, and additionally increase the excretion of hy- 'poxanthine and xanthine. The method of this invention therefore is particularly useful in the treatment and management of gout preferably by oral administration of from about to 800 mg. per day of the active products in divided doses as prescribed by the physician.

Any of the known methods for formulating thiazide products can be used in the preparation of suitable dosage forms of the active ingredients employed in the method of this invention. The following formulation is therefore provided to illustrate one of many suitable dosage forms:

DRY-FILLED CAPSULES CONTAINING 100 MG. OF ACTIVE INGREDIENT PER CAPSULE Per capsule, mg. 3-(4-pyridyl) 6 trifluoromethyl 7 sulfamoyl- 1,2,4-benzothiadiazine-1,1-dioxide 100.0 Lactose 175.0 Magnesium stearate 0.5

Capsule size No. 2.

The active ingredient is reduced to a No. 60 powder. The lactose then is also reduced to a No. 60 powder by passing through a No. 60 bolting cloth. The ingredients are combined, admixed for 10 minutes and filled into the No. 2. capsules.

The following examples illustrate methods employed to prepare the active ingredients employed in the method of this invention.

EXAMPLE 1 3- (4-pyridyl-1-methyl chloride) -6-chloro-7-sulfamoyl- 1,2,4-benzothiadiazine-1, l-dioxide A solution of 6-chloro-3-(4-pyridyl)-7-sulfamoyl-l,2,4- benzothiadiazine-1,1-dioxide (0.5 g., 0.00134 mole) in dimethylformamide (4 ml.) is treated with methyl iodide (2.0 g., 0.0142 mole) and stirred at ambient temperature for 48 hours. Following precipitation with ether and purification by reprecipitation from sodium hydroxide solution with hydrochloric acid, the product melts at 350 C.

Analysis.-Calculated for C H Cl N O S C, 36.89; H, 2.86; N, 13.24. Found: C, 37.15; H, 2.95; N, 13.24.

EXAMPLE 2 3- (2-amino-4-pyridyl) -6-chloro-7-sulfamoyl-1,2,4- benzothiadiazine-1,1-dioxide hydrochloride A solution of 6-chloro-3-(2-acetamido-4-pyridyl)-7-sulfamoyl-l,2,4-benzothiadiazine-1,1-dioxide (1.0 g., 0.0023 mole) in 6 N hydrochloric acid (50 ml.) and ethanol (50 ml.) is heated under reflux for 3 hours. The mixture is chilled and the precipitate collected and recrystallized from water giving product melting at 325-328 C.

Analysis.-Calculated for C H ClN O S -HCl: C, 33.97; H, 2.61; N, 16.51. Found: C, 34.03; H, 2.71; N, 16.36.

dissolved in a mixture of 75 ml. of ethanol and 75 ml. of concentrated ammonium hydroxide. The solution is heated under reflux for three hours then concentrated to dryness in vacuo, the residue suspended in 100 ml. of water and the product precipitated upon acidification with hydrochloric acid. The product is purified by recrystallization from a mixture of dimethylformamide and water.

By reacting 2,4-disulfamoyl-5-chloroaniline with 4- pyridine carboxylic acid chloride by the procedure described in Method A there is obtained 3-(4-pyridyl)-6- chloro-7-sulfamoyl-l,2,4-benzothiadiazine-1,1-dioxide.

Method B An intimate mixture of the orthanilamide derivative (0.01 mole) and heterocyclic carboxylic acid (0.0l mole) is heated with 20 ml. of phosphorus oxychloride for 15 minutes at 50 C. and for an additional minutes on the steam bath. The solution is cooled and poured onto ice. The product is separated and then heated on the steam bath in a mixture of ml. of ethanol and 50 ml. of concentrated ammonium hydroxide for two hours. After concentration in vacuo, the residue is treated with 50 ml. of water and the product separated by acidification with hydrochloric acid.

By reacting 2,4-disulfamoyl-5-chloroaniline and 2- methoxy-S-pyridine carboxylic acid according to the procedure described in Method B there is obtained 3-(2- methoxy-S-pyridyl)-6-chloro 7 sulfamoyl-1,2,4-benzothiadiazine-1,1-dioxide.

The products of Table I were prepared by the procedure of Method A or Method B as indicated in the table employing the orthanilamide and the heterocyclic carboxylic acid or acid halide having the substituents designated in the table. The substituents X, R, R and R of the starting materials appear unchanged in the end product, I.

TABLE I Y Y N x NH. 11 -0012: x \T H.No.s 0M1. mums NH Analysis (percent) Math 0 My. Calculated Found R 1 syn. 0. Formula C H N C H N 4-pyridyl 01 A 339-342 CIIHQF3N|O4S| 38.42 2.23 13.79 38.36 2.66 13.50 --d0 C1 A 350 ClIHlClINlOSI 35.39 1.98 13.76 35.39 2.15 13.75 d0..- Cl A 350 CIJHHCINOASI 40.36 2.87 14.48 40.35 2.90 14.43 -do-- O! A 350 C14H14N4O4S: 45.89 3.85 15.29 45.55 3.94 15.12 d0- Cl A 350 CllHllClNlOlSl 40.36 2.87 14.48 40.48 3.15 14.48 --.d0 C A 342 O1aHuN4O S 44.31 3.43 15.90 44.55 3.45 15.99 2-methyl-4-pyrid O B 340 CuHnClNtOtSa 40.36 2.87 14.48 40.21 2.91 14.48 y y y OR B 361 CUHHCINAOS! 41.95 3.27 13.98 41.64 3.33 13.67 2-methoxy-6-meth y1-4-pyr1dyl OH B 360 C1|H1:C1N405S| 40.34 3.14 13.44 40.83 3.11 13.43 2-ace tamld0-4-pyndyl 011 B 255-258 C14H;|C1N;O;S.-H,O 37.54 3.15 15.64 37.55 3.05 15.68 2,6-d1hydroxy-4-pyndyl OH B 350 CnH ClN|O S| 35.60 2.24 13.84 35.73 2.38 13.85

EXAMPLE 3 EXAMPLE 15 3-(4-pyridyl-l-oxide)-6-chloro-7-sulfamoyl-1,2,4-

benzothiadiazine- 1, l-dioxide Method A A mixture of the orthanilamide derivative (0.02 mole) and pyridine carboxylic acid chloride (0.022 mole) in 75 ml. of dioxane or other inert organic solvent is heated under reflux conditions for about 24 hours. The mixture is chilled, the solid collected, washed with cold ether and 2-methyl-3-(2-methoxy-5-pyridyl)-6-chloro-7-sulfamoyl- 3,4-dihydro-1,2,4-benzothiadiazine-1,l-dioxide EXAMPLE 16 2-methy1-3-(4-pyridyl)-6-chloro-7-sulfamoyl-3,4-dihydro- 1,2,4-benzothiadiazine-1,l-dioxide By replacing the 2-methoxy-5-pyridine carboxaldehyde employed in Example 15 by an equivalent quantity of 4-pyridine carboxaldehyde and following substantially the same procedure described in Example 15, crude product is obtained which following recrystallization from a mixture of dimethylformamide and water, melts at 215- 216 C.

Analysis.Calculated for C H ClN O S- C, 41,21; H, 3.46; N, 14.78. Found: C, 40.90; H, 3.65; N, 14.54.

By replacing the orthanilamide and the pyridine carboxaldehyde employed in Example 15 by equivalent quantities of the following reaction pairs:

(a) 2-N-methylsulfamoyl-4-sulfamoyl-S-trifiuoromethylaniline and 2-pyridyl carboxaldehyde,

(b) 2-N-methylsulfamoyl 4-sulfamoyl-S-trifluoromethylaniline and 3-pyridyl carboxaldehyde,

(c) Z-N-methylsulfamoyl-4-sulfamoyl-5-bromoaniline and 3-methyl-2-pyridyl carboxaldehyde, and

(d) 2-N-methylsulfamoyl-4-sulfamoyl-S-methylaniline and 4-pyridyl carboxaldehyde,

there is obtained, respectively:

EXAMPLE 17 2-methyl-3- Z-pyridyl) -6-trifiuoromethyl-7- sulfamoyl-3,4-

dihydro-1,2,4-benzothiadiazine-1,l-dioxide.

EXAMPLE 18 2-methyl-3-(3-pyridyl)-6-trifluoromethyl-7-sulfamoyl-3,4-

dihydro-l,2,4-benzothiadiazine-1,1-dioxide.

EXAMPLE 19 2-methy1-3-(3-methyl-2-pyridyl)-6-bromo-7-sulfamoyl- 3,4-dihydro-1,2,4-benzothiadiazine-1,1-dioxide.

EXAMPLE 20 2-methyl-3-(4-pyridyl)-6-methyl-7-sulfamol-3,4- dihydro-1,2,4-benzothiadiazine-l,l-dioxide.

Representative 3-pyridyl-benzothiadiazines were found to be effective when tested by an art recognized procedure designed to evaluate xanthine oxidase inhibiting properties of compounds. The procedure used employed the principles described in P. Pharm. Sci. 56:995 (1967), Baker et al., and was carried out in the following manner:

A reference cuvette is filled with 0.05 M pH 7.4 buffer. For the control, mix quickly in a cuvette 2 ml. hypoxanthine solution (6X10- M), 2 ml. 0.05 M pH 7.4 buffer solution, and 2 ml. Xanthine oxidase solution, and immediately record the absorbance at 292 for one minute. For the test solution, add quickly to a separate cuvette 2 ml. hypoxanthine solution (6X10- M), 2 ml. test solution, and 2 ml. oxidase solution, and immediately record the absorbance at 2921.4 for one minute. If the inhibition is less than 100%, the percent inhibition is calculated as follows:

AA control AA test AA control X 100 TABLE H N x R HzNOaS Percent inhi- R bltion e-pyridyl-l-methyl chloride 31 2-amln0-4-pyridyl I h 42 59 40 48 73 I 65 I 84 31 I 50 2-acetamido-4-pyrldyl 70 2,6-dlhydroxy-4-pyrldyl 50 it x Tm HzNOzS Percent inhi- X R R bltlon Cl CH; Z-methoxy-fi-pyrldyl- I 50 Cl CH; 4-pyridyl 30 Norn.-Concentratlon or test compound: I axis- M; 2X10- M.

What is claimed is:

1. A methodwhich comprises orally administering to a mammal having an elevated blood uric acid level a dose sufficient to lower the blood uric acid level to normal for that species of a xanthine oxidase inhibiting compound having the formula I or formula II: 3-R -5-Y-6-X-7- H NO S-1,2,4-benzothiadiazine-1,l-dioxide (I) or 2-R 3-R -6-X-7-H NO S-3A-dihydro-1,2,4 benzothiadiazinc- 1,1-dioxide (II) or the sodium or potassium salt thereof wherein X represents chloro, bromo, trifluoromethyl or C alkyl; R represents pyridyl, its lower alkyl halide quaternary ammonium salt, N-oxide or monoor di-substituted pyridyl wherein the substituents are alike or dissimilar selected from the group consisting of hydroxy, C alkyl, C alkoxy, amino, or acetylamino; and R is C alkyl, and Y represents hydrogen, chloro and C1 3 alkyl.

2. A method as claimed in claim 1 wherein the active agent has structure 11.

3. A method as claimed in claim 2 wherein in the active agent X is chloro.

4. A method as claimed in claim 2 wherein in the active agent X is chloro and R is methyl.

5. A methodas claimed in claim 2 wherein the active agent is 2 methyl-3-(2-methoxy-5-pyridyl)-6-chloro-7- sulfamoyl-3,4-dihydro-1,2,4-benzothiadiazine-1,1-dioxidei 6. A method which comprises orally administering to a mammal having an elevated blood uric acid level a dose sufficient to lower the blood uric acid level to normal for that species of 1a xanthine oxidase inhibiting compound having the formula 3-R -5-Y-6-X-7-H NO S-1,2,4-benzothiadiazine-l,1-dioxide or the sodium or potassium salt thereof wherein X represents chloro, bromo, trifluoromethyl or C; alkyl; R represents pyridyl, its lower alkyl halide quaternary ammonium salt, N-oxide or monoor di-substituted pyridyl wherein the substituents are alike or dissimilar selected from the group consisting of hydroxy, C alkyl, C alkoxy, amino or acetylamino; and Y represents hydrogen, chloro and C; alkyl.

7. A method as claimed in claim 6 wherein in the active product R is 4-pyridyl.

8. A method as claimed in claim 7 wherein in the active product Y is hydrogen.

9. A method as claimed in claim .6 wherein the active product is 3- (4-pyridyl) -6-trifluoromethyl-7-sulfamoyl- I, 2,4-benzothiadiazine-1,l-dioxide,

10. A method as claimed in claim 6 wherein the active product is 3-(4-pyridyl)-6-methyl-7-sulfamoyl-1,2,4-benzothiadiazine-l,l-dioxide.

11. A method as claimed in claim 6 wherein in the active product Y represents hydrogen and R is a monoor di-substituted-4-pyridyl.

12. A method as claimed in claim 11 wherein in the active product X is chloro.

13. A method as claimed in claim 6 wherein the active agent is 3 (2-amino-4-pyridyl-) -6-chloro-7-sulfamoyl-1,2, 4-benzothiadiazine-1,l-dioxide.

14. method as claimed in claim 6 wherein the active agent is 3-(2-methyl-4-pyridyl)-6-chloro-7-sulfamoyl-l,2, 4-benzothiadiazine-1,1-dioxide. 3 Y r 15. A method as claimed in claim 6 wherein the active agent is 3 (2-methoxy-6-methyl-4-pyridyl)-6-chloro-7- sulfamoyl-1,2,4-benzothiadiazine-1,l-dioxide. v i

No references cited. STANLEY I. FRIEDMAN, Primary Examiner 

